In plaque, bacteria are routinely subjected to acid stresses following ingestion of fermentable carbohydrates by the host. Cariogenic organisms such as the mutans streptococci can adapt physiologically to acid stress. This adaptation can occur in less than a cell generation and involves increased activities of proton-translocating F-ATPases as well as other, currently ill-defined mechanisms of coping with acidification. Thus, cariogenic bacteria not only have a high basal or constitutive level of resistance to acid stress but can increase their resistance through inducible adaptive mechanisms. Similar types of acid adaptation occur in enteric bacteria and serve to enhance resistance to killing in the acidified environment of the phagolysosome. The major focus of this application will be on physiologic and molecular characterization of the adaptive responses of mutans streptococci to acid stress, which are likely to overlap with responses to other stresses such as to lead in plaque. Acid-adapted cells of mutans streptococci can carry out glycolysis at pH values lower than the minimum for unadapted cells, and this ability in plaque would translate into enhanced potential for demineralization, i. e., enhanced cariogenicity. Plaque bacteria other than mutans streptococci can adapt to acid stress, and this adaptation, which includes derepression of the arginine deiminase system in organisms such as Streptococcus sanguis, is likely to be of major importance in overall plaque ecology. However, the orientation in this application is primarily to mutans streptococci. The three specific aims of the project are: l) to develop a more complete physiological definition of adaptation to acid stress in mutans streptococci and closely related bacteria, 2) to identify and characterize acid-regulated proteins and genes of mutans streptococci, and 3) to carry out molecular genetic analysis of the regulation and function of major stress response proteins in mutans streptococci. The coordinated efforts of the three laboratories involved in this project will be supplemented by interactions within the program, especially in relation to effects of heavy metals and salivary peptides on cariogenicity. A long term objective of the work is to design means to upset the responses and thereby to lower plaque cariogenicity.